Project Summary Sj?gren?s syndrome (SS) is a chronic autoimmune disease that inflicts damage and dysfunction to salivary and lacrimal glands and many other organs, resulting in dry mouth, dry eyes and various systemic health problems. SS affects the oral and systemic health and life quality of 2-4 million Americans, with no cure or effective biological therapies currently available. An urgent need in SS research is to better understand the causes and pathogenic processes of this highly complex and multi-factorial disease, and to identify critical new therapeutic targets for the development of effective and targeted therapies for this high-impact autoimmune disease. The goal of this project is to define the previously unexplored role of cytokine interleukin-22 (IL-22) in vivo in the pathogenic development of salivary gland disorder in SS. Our preliminary studies have generated strong evidence that excessive IL-22, a cytokine with well-documented epithelial tissue-protective function, can cause salivary gland tissue damage and secretory hypofunction in both normal and SS-prone mice. In this proposed study, we will test the central hypothesize that in SS disease, endogenously produced IL-22 critically contributes to the pathological changes and secretory dysfunction of the salivary glands. We will test this hypothesis in two mouse models of human SS disease. In Aim 1 of the study, we will determine the in vivo function of endogenous IL-22 in the development of salivary gland pathologies and dysfunction through antibody-mediated neutralization of IL-22 in the non-obese diabetic mouse, a spontaneous SS disease model. In Aim 2, we will define the role of endogenous IL-22 in SS by using IL-22 gene-deficient mice and an autoantigen-induced SS disease model. In both aims, we will examine how the ablation of endogenous IL-22 activity affects the development of SS-like salivary gland disorder by assessing the damage, inflammation, salivary secretion and molecular changes of salivary gland tissues. Successful completion of this study will for the first time define the salivary gland- and SS disease-specific role of IL-22. It will also pave the foundation for further investigation and elucidation of the biology, functional specificity and plasticity, and therapeutic potential of IL-22 in SS disease and various other epithelial tissue autoimmune inflammatory disorders.